Morpholine substituted esters



Patented Aug. 17, 1948 MORPHOLINE' SUBSTITUTED ESTERS Lee C. Cheney, Detroit, and William G. Bywater,

Grosse Pointe Woods, Mich., assignors to Parke, Davis .& Company, Detroit, Micln, av corporation of Michigan No Drawing. Application July 5,1940, Serial No. 344,136

where A represents a member of the group con.- sisting of straight chain. and branched. chain alkylene residues.

The invention includes also salts, of the com.-

pounds'of the above general formula with acids HX where X is an anion of an organic or inorganic acid. The preferred salts arethoseof non.- oxidizing, non-toxic organic. or inorganic acids which are Water-soluble. The invention is, more fully illustrated by the followingexamples:

Example i.--c-4-morpholinoethyl diphenylacetat'e and salts A. Diphenylacetyl chloride is. prepared, by. refluxing 21.2 g. (0.1 mole) of diphenylacetic. acid with 40 g. (0.36mo1e). ofithionyl chloride for one, hour. The mass, is allowed to cool and excess. thionyl chloride removed in vacuo. The crude. acid chloride cooled in an ice bath, is treatediwith' 13.12 grams (0.1 mole) of pi-morpholinoethanol' without a diluent. To complete the exothermic reaction,,the mixture is heated in an oil bath at 120 for 1.75 hours and to isolate the desired ester hydrochloride, the brown solid is dissolved in 600-700 ml. of hot ethyl acetateandv allowed to crystallize. After three recrystallizations from ethyl acetate, the ester hydrochloride is found. to melt at 136-137 C. (corr.) Micro-Dumas nitrogen. analysis gives N, 3.85" and 3.95%, while the calculated nitrogen contentior C'zoI-IirOsNClt B. Diphenylacetylchioride is prepared as in A from 63.7 g. (0.3 mole),- of. diphenylacetic acid. It is dissolved in 50 ml. of sodium-dried dioxane and added during 15 minutes toa stirred: solution 50' ml. of sodium-dried dioxane.

rendered basic with sodium carbonate solution to secure an ether solution of B4-morpholinoethyl diphenylacetate. It (ca. 700 ml.) is washed thrice with water and dried over anhydrous potassium carbonate (which is eventually removed by filtration) and is employed to prepare watersoluble, therapeutically useful. salts of this ester, but if desirable the ester itself may be secured in pure form as an oil by distilling under reduced pressure.

To obtain the hydrochloride, absolute alcoholic hydrogen chloride is. added to the. ether solution and the oily hydrochloride. which separates is induced to crystallize by rubbing with a glassxrod. fl-l-morpholinoethyl. diphenylacetate. hydrochlo ride havingtheformula oi onion:

separates as white crystals melting at 1365-1375 which after. recrystallization from ethyl acetate melts atl37j5-138" (corn).

The hydrobromide is. prepared in a similar manner by passing gaseous hydrogen bromide, generated from. bromine and boiling tetralin, directly into the ether solution. or by treating the ether solution with 48% aqueous hyd'robromic acid. In the latter case the mixture is evaporated to dryness under reduced pressure, the product is taken up in boiling absolute: alcohol and then allowed" to crystallize. The fi l morpholinoethyl diphenylacetate hydrobromide is obtained as small White hygroscopiccrystals having the formula H omega onoooomomn Br omen:

which melts at 119-120 (corr.; sealed tube).

C. If instead of one equivalent of B-4-morpholinoethanol, twoor more equivalentsare employed-in dioxane solution, theester is secured directly in improved-yields..- ,li-l-morpholinoethyl diphenylacetate is also secured by the actionof Example 2.--y-4-mor.pholinopropyl diphenylacetate and its. hydrochloride The required y-el-morpholinopropanol is synthesizedby heating 94i6'g. (-1 mole) of trimethylene chlorohydrin with 174.3 g. (2 moles) of morpholine first to 100-105 for 1.5 hours, then to 125-130 for one-half hour in an oil bath. It is isolated from the reaction product by saturating the aqueous phase with solid sodium hydroxide. The resulting oil is dried with solid sodium hydroxide and distilled at reduced pressure. The yield of 7-4-morpholinopropanol by this procedure is 109.4 g. (75.2% of the theoretical), boiling at 147-149 under 21 mm. pressure and having n =1.4762; n =1.4743. This amino alcohol has been described by Gardner and Haennl (J. Am. Chem. Soc., 53, 2763 (1931)) who prepared it from 3-aminopropanol and p,c'-dichlorodiethyl ether.

Diphenylacetyl chloride is prepared according to the method given in Example 1 from 42.5 g, (0.2 mole) of diphenylacetic acid, dissolved in 200 ml. of sodium-dried benzene and treated in four portions with a solution of 29.3 g. (0.2 mole) of y-4-morpholinopropanol in 50 ml. of dry benzene. The mixture is allowed to stand overnight, and is then refluxed in a water bath for 2 hours. Upon cooling the dark-brown two-phase system, the hydrochloride of r-4-morpholinopropyl diphenylacetate separates which after recrystallization from ethyl acetate weighs 17 g. and melts at 119.5-120 C. (corn). Anal-Cale. for C21H27O3NC1: N, 3.72%. Found: 3.77 and 3.71%.

This ester hydrochloride is readily soluble in water and has the following formula:

H CHQGHI oncooomcmcm o The free base is obtained by reaction of the aqueous solutions of the salt with an excess of saturated sodium carbonate solution, extracting with ether and distilling in vacuo after removal of ether from the dried solution. It is secured as a slightly yellow, viscous oil which boils at 223-227 at,1.25, mm. pressure.

Example 3. -4-morpholirzobutyl diphenylacetate hydrochloride {-4-morpholino-n-butanol is secured by heat- Q omen,

CHCOOCHaCHnCHaCHzN O.HO1

CHaC a It melts at 118-119 (corn) after twice recrystallizing from absolute alcohol-ether and then from ethyl acetate, separating from ethyl acetate in small white crystals. Anal-Cale. for C22H2aO3NC1: N, 3.59. Found; N, 3.55 and 3.53.

Example 4.e-methyl-p-4-morpholinoethyl diphenylacetate hydrochloride To diphenylacetyl chloride from 42.5 g. (0.2

mole) of diphenyl acetic acid, dissolved in 200 ml. of dry acetone, cooled in an ice bath, is added dropwise 30.4 g. (0.21 mole) of a-rnethyl-B-4- morpholinoethanol. When all the alcohol is added, the suspension is stirred at room temperature for 6 hours. The pale pink crystals, removedirom the solution by filtration, are twice recrystallized from absolute alcohol to secure a 49.6% yield of e-methyl-fi-4-morpholinoethyl diphenylacetate hydrochloride,

Q on; n onions cnooor znorm 0 Q 01 CHflCi which melts at 214.5-215 C. (corn). Anal. Calc. for C21H2603NC1Z N, 3.72%. Found: N, 3.72 and 3.78%.

Example 5.5-methyl-fi-4-morpholinopropyl dipheng Zacetate hydrochloride A mixture of 75.1 g. (1 mole) of isopropanol amine, 150 g. (1.05 mole) of id-dichlorodiethyl ether and 208 g. (1.5 moles) of powdered anhydrous potassium carbonate, contained in a 1-liter flask provided with a reflux condenser and stirrer, is heated in an oil bath. The temperature must be raised to 170 before a vigorous reaction ensues. Removal of the bath for 25 minutes permits the evolution of carbon dioxide to moderate, then the mixture is heated at 170 for 5.3 hours and allowed to stand overnight. The semi-solid mass is warmed and broken up, then extracted with 670 ml. of benzene in four portions. The salt is dissolved in a minimum volume of water and twice extracted with benzene. The combined extracts are dried with calcium sulfate and distilled. B-methyl-[3-4-morpholino-n-propanol distill at -116 at 2 mm. pressure and melts at 59-50 (corn). Anal.'-Calc. for CaI-IrzOeN: N, 8.80. Found: N, 8.95 and 9.02.

Condensation of the fl-methyl-B-4-morpholinon-pro'panol with diphenylacetyl chloride accord-.

ing to the method described in Example 2, produces ,p-methyl-fl-4-morpholino-n-propyl diphenylacetate hydrochloride having the following formula:

The yield is 72.2% of crystals 'melting at 123.5-1245 (corn) which melt one degree higher after one crystallization from ethyl acetate.

Anal.-Calc. for CzzHzaOsNCl: N, 3.59%. Found: N, 3.64 and 3.55%. r

Example 6.-p,p-dimethyl-y-4-morpholinopropyl diphenylacetate V on; E i onion, CHCOOCHzJJN o on, (:1 onion,

acumen vaouoi, and; the: viscous. residue: dissolved. in; hot: water. The cooled solutioneis.extractedtwicawith: ether, made alkaline; withisoriium; carbonate. and the resulting free base extracted with ether. The ether extractis washed thrice with 150 mLLportions of" water anddried over anhydrous potassium carbonate. Evaporation of theether yields the desired amino ester as a solid having the formula.

which when crystallized from petroleum ether, melts at 54157-5515 (:corr-z)... Ahab-Cale. for C23H29O3N: N, 3.82%. Found; N, 3.86%.

It, is? not essential to isolate the base since therapeutically useful salts of it" may be; made directly from theether solution as described in Example 1, part B; or the desired; acid may be added directly; to, the; solution and. the resulting salt isolated by complete removal or by concentration of the ether solution. Thehydrochloride salt ofthe' morpholino-alkyl ester describedl in example melts at 149.5450? (Icorr.)'...

Example,7 -l?repdrdtion of; y; thmorpholinolmhexyl diphenylacetate hydrochloride A.mixture oi..26.5 grams (0.l09.mole), of hexamethylene bromide, 2715' grams. (0.11 mole) of. pulverized potassium v diphenylacetat'eandj IOOfml. of'sodium-dried xylene is efficiently stirred: and. refluxed in a wax bath maintained at I70 18'0" for 5 or 6 hours.

The mixture is cooled and 19.2 grams (0.22 mole) of morpholine are introduced. The stirred mixture is refluxed at 155-165 for about 2 /4 hours, cooled and decanted. The residue is extracted with 100 ml. of boiling xylene. The combined xylene solutions are filtered and the cold xylene solution extracted with dilute hydrochloric acid. The acid extract is cooled in ice, extracted twice with ether and then rendered basic with saturated sodium carbonate solution. The liberatecl base is taken up in ether and the ether solution is washed 3 times with cold water to remove all morpholine. The solution can be rapidly dried by mechanically shaking it over anhydrous potassium carbonate for 1 hours. The hydrochloride is precipitated as an oil by the addition of an excess of 4.88 molar absolute alcoholic hydrochloric acid. Crystallization can be induced by cooling the oil in an ice-salt bath and rubbing the oil against the container with a glass rod.

The crystals are filtered off and dried to yield about grams of crude hydrochloride of melting point 104-107 C. Two crystallizations from anhydrous isopropanol and then two from ethyl acetate give white micro crystals of melting point 113-1l4 C. (corn) of pure -(4-morpholino)-nheXyl diphenylacetate hydrochloride. The reactions involved in this example may be indicated by the following diagram:

w-isobutylay dmorpholinopmpiils'.diplienylacca tatahayingwheatommla' V omen-am...

cHcoohHoHioHiN CHiC- n Some-.: of the subjectematter-disclosed herein is also disclosedand claimed in our coperrding applications, Serial No. 514,162, filed December 13, 1943, now Patent No. 2,374,525, issued April 24, 1945, and Serial No. 542,262, filed June 26, 1944, now Patent No. 2,398,410, issued April 16,1946...

Whatweclaimas ourinvention-is'g' v 1. A morpholine substituted water=solubieester sal'tofthe'iormula H cmcrnf GECQQQHiQHiN wherein X represents an anion of a non-oxidizing, non-toxic acid.

2. The compound having the formula Q E CHCOOOHaCHzN o which is soluble in water and has powerful antispasmodic action.

3. The compound having the formula Q H onion,

one o o cmomomr y (al CHzCfi:

which is soluble in water and has powerful antispasmodic action.

4. Compounds selected from the group consisting of esters of the formula,

where A represents a member of the group consisting of straight chain and branched chain alkylene residues, and the acid addition salts of said esters.

5. Compounds selected from the group consist- 7 i 8 in of water-soiubie acid addition salts of aii- Where A represents alkylene residue and acid phatic esters having the formula, addition salts of said esters.

- 8. A compound of the formula I I GHQ-CH: v g '7 CHOOOCHaCHg-N o CHCO0-AN 0 CHPOQ LEE C. CHENEY.

U emcee WILLIAM G. BYWATER.

where A represents a. member of the group cori- REFERENCES CITED sisting' of straight, chem: andbranched chain alkylene residues and X represents an anion f The foliowing references are of record in the anon-oxidizing non-toxic water-solubiiizing acid. 15 file of Patent:

6. Amorpholine substituted water-solub1e ester 4 V UNITED STATES P T salt or the formula Number Name Date 615.488 Knorr Dec. 6, 1898 2,079.962 Miescher May 11, 1937 H CHPCH, 20 2,138,763 Graves Nov. 29, 193a cncoocmcmcml i 0 7 FOREIGN PATENTS I v x CHz-CHz Number Country Date 433,704 Great Britain 193a 655,404, Germany 1938 656,784 Germany 1938 where X represents an anion of anon-oxidizing 657,526 Germany 1933 ig e1 t d f OTHER REFERENCES ompoun s s ec e rom e grou consisting of the esters of the formula p v 30 Jour. Amer. Chem. 500., vol. 53, DD. 2763-9;

ibicL, vol. 55, pp. 365-70. CHVCH, Richter, Chemie der Kohlenstoff Verbindungen.

cn-c OO-A 0 VOL p. 274 (1931) 

